Despite advancements made in treatment and diagnosis, cancer remains the second leading cause of mortality in the United States, superseded only by heart disease. Solid tumors account for more than 85% of cancer mortality. Currently, the primary treatment modality for solid tumors is cytoreductive surgery followed by adjuvant chemotherapy and/or radiotherapy. While this strategy has been successfully employed in a number of patients, it is accompanied by cytotoxicity to normal cells and tissues, and the development of multidrug resistance (MDR).
Targeted cancer therapies offer the potential to improve the treatment of solid tumors. By targeting therapeutic agents to solid tumors, cytotoxicity to normal cells and tissues may be minimized. In addition, targeted therapies provide the opportunity to more rigorously control the concentration of therapeutic agent at the site of a tumor, potentially limiting the emergence of drug resistance.
Nanoparticles (NPs) have been explored for the targeted delivery of therapeutic agents to solid tumors. The larger size of nanoparticles, as compared to conventional small molecule cancer therapeutics, allows them to preferentially accumulate in solid tumors by the enhanced permeability and retention (EPR) effect. The EPR effect is a consequence of the abnormal vasculature frequently associated with solid tumors. The vasculature of tumors is typically characterized by blood vessels containing poorly-aligned defective endothelial cells with wide fenestrations. As a result, nanoparticles with an average particle size of between about 100 nm to 200 nm can preferentially extravasate out of the leaky regions of the tumor vasculature, and accumulate within the solid tumor. In addition, the lack of lymphatics in the tumor region prevent the nanoparticles from being efficiently filtered and removed, increasing the residence time of the nanoparticles within the tumor relative to residence in normal tissue and the vasculature.
In view of the potential of nanoparticles to passively target therapies via the EPR effect, nanoparticle formulations have been investigated for the delivery of small molecule therapeutic agents to solid tumors, including two FDA-approved nanoparticle-based therapeutics—DOXIL® (an 100 nm PEGylated liposomal form of doxorubicin) and ABRAXANE® (an 130 nm albumin-bound paclitaxel nanoparticle). While these formulations exhibit improved pharmacokinetic properties and reduced adverse effects, existing nanoparticle formulations have provided only modest survival benefits. The limited efficacy of these existing nanoparticle formulations stems from their inability to effectively deliver the therapeutic agents throughout the solid tumor.
Systemic delivery of therapeutic agents to solid tumors is a three step process: (1) blood-borne delivery of the therapeutic agent to different regions of the tumor; (2) transport of the therapeutic agent across the vessel wall into the solid tumor; and (3) passage of the therapeutic agent from the tumor tissue adjacent to the vasculature to the tumor cells via diffusion through the interstitial space.
Abnormalities in the tumor vasculature lead to highly heterogeneous vascular perfusion throughout solid tumors. While the microvascular density is often high at the invasive edge of tumors, the tumor center is often unperfused. As a result, diffusion through the interstitial matrix is the primary mode for drug transport to the poorly perfused tumor center and the nanoparticles are unable to effectively diffuse through the dense interstitial matrix of the solid tumor—a complex assembly of collagen, glycosaminoglycans, and proteoglycans—to reach the tumor cells within the tumor center.
As a consequence, existing nanoparticle formulations are limited in their ability to deliver a therapeutic agent throughout the entire tumor. For example, in the case of DOXIL®, upon accumulation in a solid tumor via the EPR effect, the liposomal particles are unable to diffuse through the dense interstitial matrix of the tumor and remain trapped close to the tumor vasculature. The liposomes trapped near the vasculature release doxorubicin; however, in spite of its relatively low molecular weight (approximately 400 Da), the doxorubicin cannot migrate far from the particles due to avid binding to DNA and sequestration in acidic endosomes of perivascular tumor cells.
As a consequence, existing nanoparticle formulations tend to produce heterogeneous therapeutic effects in solid tumors. The nanoparticle formulations deliver an effective amount of the therapeutic agent near the surface of the tumor where the leaky vasculatures are located; however, effective amounts of the therapeutic agents are not delivered to the cells in the tumor center. This is particularly problematic because the hostile microenvironment of the tumor center (characterized by low pH and low pO2) often harbors the most aggressive tumor cells. As a result, the tumor will regenerate if the cells in the tumor center are not eliminated. Moreover, exposure of the tumor cells to a sublethal concentration of the therapeutic agent can facilitate the development of drug resistance in the remaining cell lines. As a result, existing nanoparticle formulations have thus far provided only modest survival benefits when used to treat solid tumors.
Therefore, it is an object of the invention to provide improved formulations for the targeted treatment of solid tumors.
It is also an object of the invention to provide polymer-drug conjugates capable of delivering an effective amount of one or more active agents to tumor cells throughout the solid tumor.
It is a further object of the invention to provide improved methods of treating solid tumors, including malignant tumors.